Huang Yutang, Dai Yi, Wen Chunjie, He Shuai, Shi Jingjing, Zhao Dezhang, Wu Lanxiang, Zhou Honghao
Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China.
Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China; Wangjia Community Health Service Center, Chongqing 401120, China.
Mol Ther Nucleic Acids. 2020 Sep 4;21:885-899. doi: 10.1016/j.omtn.2020.07.027. Epub 2020 Jul 25.
Gefitinib is a first-line treatment for patients with non-small-cell lung cancer (NSCLC), but acquired resistance is a major obstacle to its therapeutic efficacy, and the underlying mechanisms are not fully elucidated. Recent studies have indicated that circular RNAs play a crucial role in chemoresistance, but their expression and function in NSCLC cells with acquired resistance to gefitinib are largely unknown. In this study, we determined that circSETD3 was significantly upregulated in gefitinib-resistant NSCLC cell lines and the plasma of gefitinib-resistant NSCLC patients. circSETD3 markedly decreased the gefitinib sensitivity of NSCLC cells both in vitro and in nude mice xenografts. It could directly bind to miR-520h and lead to the upregulation of ATP-binding cassette subfamily G member 2 (ABCG2), an efflux transporter of gefitinib, resulting in a reduced intracellular gefitinib concentration. Moreover, we reported that the downregulation of serine/arginine splicing factor 1 (SRSF1) contributed to, at least in part, the increased expression of circSETD3 in NSCLC cells with acquired resistance to gefitinib. Taken together, our findings indicated that circSETD3 may serve as a prognostic biomarker and a potential therapeutic target for acquired resistance to gefitinib in NSCLC.
吉非替尼是治疗非小细胞肺癌（NSCLC）患者的一线药物，但获得性耐药是其治疗效果的主要障碍，其潜在机制尚未完全阐明。最近的研究表明，环状RNA在化疗耐药中起关键作用，但它们在对吉非替尼产生获得性耐药的NSCLC细胞中的表达和功能大多未知。在本研究中，我们发现circSETD3在吉非替尼耐药的NSCLC细胞系和吉非替尼耐药的NSCLC患者血浆中显著上调。circSETD3在体外和裸鼠异种移植模型中均显著降低了NSCLC细胞对吉非替尼的敏感性。它可以直接与miR-520h结合，导致吉非替尼的外排转运蛋白ATP结合盒亚家族G成员2（ABCG2）上调，从而降低细胞内吉非替尼浓度。此外，我们报道丝氨酸/精氨酸剪接因子1（SRSF1）的下调至少部分促成了对吉非替尼产生获得性耐药的NSCLC细胞中circSETD3表达的增加。综上所述，我们的研究结果表明，circSETD3可能作为NSCLC中吉非替尼获得性耐药的预后生物标志物和潜在治疗靶点。
